Inside-out neuropharmacology of nicotinic drugs

• Nicotinic ligands enter endoplasmic reticulum (ER) and bind to some nicotinic receptors (AChRs).
• This “pharmacological chaperoning” alters traffic within early secretory pathways.
• As a result, chronic exposure to nicotinic ligands upregulates some AChRs.
• These results of intra-organellar binding are termed “inside-out pharmacology”.
• “Inside-out” effects also modify ER stress and the unfolded protein response.

Upregulation of neuronal nicotinic acetylcholine receptors (AChRs) is a venerable result of chronic exposure to nicotine; but it is one of several consequences of pharmacological chaperoning by nicotine and by some other nicotinic ligands, especially agonists. Nicotinic ligands permeate through cell membranes, bind to immature AChR oligomers, elicit incompletely understood conformational reorganizations, increase the interaction between adjacent AChR subunits, and enhance the maturation process toward stable AChR pentamers. These changes and stabilizations in turn lead to increases in both anterograde and retrograde traffic within the early secretory pathway. In addition to the eventual upregulation of AChRs at the plasma membrane, other effects of pharmacological chaperoning include modifications to endoplasmic reticulum stress and to the unfolded protein response. Because these processes depend on pharmacological chaperoning within intracellular organelles, we group them as “inside-out pharmacology”. This term contrasts with the better-known, acute, “outside-in” effects of activating and desensitizing plasma membrane AChRs. We review current knowledge concerning the mechanisms and consequences of inside-out pharmacology.This article is part of the Special Issue entitled ‘The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition’.